Control of arthropods in animals

ABSTRACT

A method of controlling parasites in or on an animal comprising orally administering to the animal a parasitically effective, substantially non-emetic 1-arylpyrazole.

This application claims the priority of U.S. Provisional Application No. 60/111,857, filed Dec. 11, 1998, and of U.S. Provisional Application No. 60/140,680, filed Jun. 24, 1999, both incorporated by reference herein in their entireties and relied upon.

The present invention relates to a method of control of parasites in animals, compositions comprising a compound effective for said control and new compounds effective against parasites.

It is generally a goal of agronomists and veterinarians to possess sufficient means to control pests, particularly arthropods, when they attempt to invade or attack mammals, particularly domestic animals and/or livestock. A classical method of controlling such pests has been the use of topical and/or systemic pesticides on or in the domestic animal which is being attacked. Generally effective treatments include the oral administration of insect growth regulators, such as lufenuron, or antihelminth compounds such as an ivermectin or an avermectin, or the topical application of the insecticide fipronil. It is advantageous to apply pesticides to animals in oral form so as to prevent the possible contamination of humans or the surrounding environment.

It is an object of the present invention to provide new pesticides which may be used in domestic animals.

Another object of the invention is to provide safer pesticides for domestic animals.

Another object of the invention is to provide new pesticides for domestic animals that may be used in lower doses than existing pesticides.

These objects are met in whole or in part by the present invention.

The present invention provides a method of controlling parasites in or on an animal comprising administering orally to the animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole of formula (I): ##STR1## wherein

R₁ is cyano, acetyl, C(S)NH₂, alkyl, haloalkyl, C(═NOH)NH₂ or C(═NNH₂)NH₂ ;

R₂ is S(O)_(n) R₃, C₂ -C₃ alkenyl, C₂ -C₃ haloalkenyl, cycloalkyl, halocycloalkyl or C₂ -C₃ alkynyl;

R₃ is alkyl or haloalkyl;

R₄ is --N═C(R₅)--Z--R₆, --N═C(R₅)--N(R₇)--R₈, or --N(R₉)--C(R₅)═NR₆ ;

R₅ is hydrogen, alkyl, or alkyl substituted by halogen, alkoxy, haloalkoxy or --S(O)_(m) R₁₅ ;

R₆ and R₇ each independently represent hydrogen, alkyl, C₃ -C₅ alkenyl or C₃ -C₅ alkynyl; or

alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; or

R₆ and R₇ may form together with the nitrogen to which they are attached a 3 to 7 membered ring which may additionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur;

R₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, R₁₄ CO-- or --S(O)_(t) R₁₀ ;

R₉, R₁₀ and R₁₄ are alkyl or haloalkyl;

R₁₁ and R₁₂ are independently selected from halogen, hydrogen, CN and NO₂ ;

R₁₃ is selected from halogen, haloalkyl, haloalkoxy, --S(O)_(q) CF₃, and --SF₅ ;

R₁₅ is alkyl or haloalkyl;

X is selected from nitrogen and C--R₁₂ ;

Z is O, S(O)_(a), or NR₇ ;

a, m, n and q are independently selected from 0, 1, and 2; and

t is 0 or 2;

and veterinarily acceptable salts thereof.

In another aspect, the present invention provides a method of controlling parasites in or on an animal comprising administering orally to the animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole of formula (XX): ##STR2## wherein

R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, alkyl, C(═NOH)NH₂ or C(═NNH₂)NH₂ ;

R₂₀₂ is S(O)_(h) R₂₀₃, C₂ -C₃ alkenyl, C₂ -C₃ haloalkenyl, cycloalkyl, halocycloalkyl or C₂ -C₃ alkynyl;

R₂₀₃ is alkyl or haloalkyl;

R₂₀₄ is --N(R₂₀₅)C(O)CR₂₀₆ R₂₀₇ R₂₀₈, --N(R₂₀₅)C(O)aryl, or --N(R₂₀₅)C(O)OR₂₀₇ ;

R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl cycloalkylalkyl, halocycloalkylalkyl, alkoxyalkyl, haloalkoxyalkyl, C₃ -C₅ alkenyl, C₃ -C₅ haloalkenyl, C₃ -C₅ alkynyl, C₃ -C₅ haloalkynyl;

R₂₀₆ is hydrogen, halogen, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, formyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsufinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino, di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy, alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy, or arylalkoxy;

R₂₀₇ and R₂₀₈ are independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; or R₂₀₇ and R₂₀₈ may form together with the carbon to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;

X₁ is selected from nitrogen and C--R₂₁₂ ;

R₂₁₁ and R₂₁₂ are independently selected from halogen, hydrogen, CN and NO₂ ;

R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, --S(O)_(k) CF₃, and --SF₅ ; and

h and k are independently selected from 0, 1, and 2;

and veterinarily acceptable salts thereof.

By the term "veterinarily acceptable salts" is meant salts the anions of which are known and accepted in the art for the formation of salts for veterinary use. Suitable acid addition salts, e.g. formed by compounds of formulae (I) and (XX) containing a basic nitrogen atom, e.g. an amino group, include salts with inorganic acids, for example hydrochlorides, sulphates, phosphates and nitrates and salts with organic acids for example acetic acid.

Unless otherwise specific, alkyl and alkoxy groups here and throughout this specification are generally lower alkyl and alkoxy groups, that is having from one to six carbon atoms, preferably from one to four carbon atoms. Generally, the haloalkyl, haloalkoxy and alkylamino groups have from one to four carbon atoms. The haloalkyl and haloalkoxy groups can bear one or more halogen atoms, preferred groups of this type include --CF₃ and --OCF₃ --. Cycloalkyl groups generally have from 3 to 6 carbon atoms, preferably from 3 to 5 carbon atoms and may be substituted by one or more halogen atoms. Alkenyl, haloalkenyl, alkynyl, and haloalkynyl groups generally contain from 3 to 5 carbon atoms. By the term aryl is generally meant phenyl, pyridyl, furyl, and thiophenyl (thienyl), each of which is optionally substituted by one or more halogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, hydroxy, amino, alkylamino or dialkylamino. In compounds of formula (I), by the term substituted alkyl is meant alkyl which is substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two. Preferably in compounds of formula (I), alkyl groups are generally substituted by from one to five halogen atoms, preferably from one to three halogen atoms. Chlorine and fluorine atoms are preferred.

The above definitions of alkyl, alkoxy and various other groups of course pertain not only to those radicals themselves but also to those portions of larger radicals.

Compounds of formula (I) wherein R₄ is --N═C(R₅)--Z--R₆, Z is NR₇ and R₆ represents a hydrogen atom may exist at the tautomeric double bond isomer form --NH--C(R₅)═N--R₇. It is to be understood that both such forms are embraced by the present invention.

In compounds of formula (XX) the following examples of radicals are provided:

An example of cycloalkylalkyl is cyclopropylmethyl;

an example of cycloalkoxy is cyclopropyloxy;

an example of alkoxyalkyl is CH₃ OCH₂ --;

an example of alkoxyalkoxy is CH₃ OCH₂ O--;

An example of alkoxyalkoxyalkoxy is CH₃ OCH₂ OCH₂ O--;

An example of aryloxy is the phenoxy radical; and

An example of the arylalkoxy radical is benzyloxy or 2-phenylethoxy.

Generally, in dialkylamino or di(haloalkyl)amino radicals, the alkyl and haloalkyl groups on nitrogen may be chosen independently of one another.

It is also to be understood that enantiomeric and diastereomeric forms of the compounds of formula (I) and (XX) and salts thereof are embraced by the present invention. Compounds of formula (I) may be generally prepared according to known processes, for example as described in European Patent Application 511845 or other processes according to the knowledge of a man skilled in the art of chemical synthesis.

By the term non-emetic is meant a compound that does not generally elicit emesis from the animal when a protective, preventative or cleaning dose is administered to the animal. By the term emesis is meant vomiting. Generally an emetic substance elicits emesis in less than 24 hours after administration, preferably less than 8 hours, more preferably less than 2 hours. Generally when the compounds of the invention are administered to a population of animals, more than 70% of the animals are free of emesis, preferably more than 80%, most preferably more than 90%.

A preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano or alkyl;

R₂ is S(O)_(n) R₃ ;

R₃ is an alkyl or haloalkyl;

R₄ is --N═C(R₅)--Z--R₆ ;

R₅ is hydrogen, alkyl or haloalkyl;

Z is O, S(O)_(a), or NR₇ ;

R₆ and R₇ are independently selected from hydrogen and unsubstituted or substituted alkyl; or

R₆ and R₇ may form together with the nitrogen to which they are attached a 3 to 7 membered ring which may additionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur;

X is selected from nitrogen and C--R₁₂ ;

R₁₁ and R₁₂ are independently selected from halogen, hydrogen, CN and NO₂ ;

R₁₃ is selected from halogen, haloalkyl, haloalkoxy, --S(O)_(q) CF₃, and --SF₅ ;

a, n and q are independently selected from 0, 1, and 2.

Preferably R₆ is alkyl which is substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, sulfide, sulfoxide, sulfone, or phenyl or pyridyl moieties of which each phenyl or pyridyl moiety is optionally substituted with one or more groups selected from halo, nitro, and alkyl.

Preferably the method of the invention has one or more of the following features:

R₁ is cyano;

R₄ is --N═C(R₅)--Z--R₆ and Z is --NR₇ ;

X is C--R₁₂ ; R₁₁ and R₁₂ represent a chlorine atom; and R₁₃ is CF₃, OCF₃ or --SF₅ ;

R₁₂ is --S(O)_(n) CF₃ and n is 0, 1, or 2.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano or alkyl; R₄ is --N═C(R₅)--Z--R₆ ; and R₅ is hydrogen or C₁ -C₃ alkyl.

The compounds of formula (I) for use in the control of parasites in animals, preferably have one or more of the following features:

R₁ is cyano or methyl;

R₃ is halomethyl (preferably CF₃);

R₁₁ and R₁₂ each independently represent a halogen atom;

X is C--R₁₂ ;

R₁₃ is haloalkyl (preferably CF₃), haloalkoxy (preferably OCF₃), or --SF₅ ; or

n is 0, 1 or 2 (preferably 0 or 1).

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano;

R₂ is S(O)_(n) R₃ ;

R₃ is halomethyl;

R₄ is --N═C(R₅)--Z--R₆ ;

Z is NR₇ ;

R₅ is hydrogen or alkyl;

R₆ and R₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or alkyl substituted with phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;

X is selected from nitrogen and C--R₁₂ ;

R₁₁ and R₁₂ each independently represent a halogen atom;

R₁₃ is selected from haloalkyl, haloalkoxy and --SF₅ ;

R₁₅ is alkyl or haloalkyl; and

m and n are independently selected from 0, 1, and 2.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals is that wherein:

R₁ is cyano;

R₂ is S(O)_(n) CF₃ ;

R₄ is --N═C(R₅)--Z--R₆ or --N═C(R₅)--N(R₇)--R₈ ;

Z is NR₇ ;

R₅ is hydrogen or alkyl;

R₆ and R₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;

R₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or --S(O)_(t) R₁₀ ;

X is selected from nitrogen and C--R₁₂ ;

R₁₀ and R₁₅ independently represent alkyl or haloalkyl;

R₁₁ and R₁₂ each represent a chlorine atom;

R₁₃ is CF₃ or --SF₅ ; and

m and n are 0, 1 or 2; and t is 0 or 2.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano;

R₂ is S(O)_(n) CF₃ ;

R₄ is --N═C(R₅)--Z--R₆ ;

Z is NR₇ ;

R₅ is hydrogen or methyl;

R₆ and R₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;

X is C--R₁₂ ;

R₁₁ and R₁₂ each represent a chlorine atom;

R₁₃ is CF₃ or --SF₅ ;

R₁₅ is alkyl or haloalkyl;

m is zero, one or two; and

n is 0 or 1.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano;

R₂ is S(O)_(n) CF₃ ;

R₄ is --N═C(R₅)--Z--R₆ ;

Z is NR₇ ;

R₅ and R₇ each represent a hydrogen atom;

R₆ is alkyl or haloalkyl;

X is C--R₁₂ ;

R₁₁ and R₁₂ each represent a chlorine atom;

R₁₃ is CF₃ or --SF₅ ; and

n is 0.

Compounds of formula (XX) which are preferred according to the present invention are those wherein:

wherein:

R₂₀₁ is cyano;

R₂₀₂ is S(O)_(h) R₂₀₃ ;

R₂₀₃ is alkyl or haloalkyl;

R₂₀₄ is --N(R₂₀₅)C(O)CR₂₀₆ R₂₀₇ R₂₀₈ ;

R₂₀₅ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl and halocycloalkylalkyl;

R₂₀₆ is alkoxy, haloalkoxy, or hydrogen;

R₂₀₇ and R₂₀₈ are independently hydrogen, alkyl, or haloalkyl; or

R₂₀₇ and R₂₀₈ may form together with the carbon to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;

X₁ is selected from nitrogen and C--R₂₁₂ ;

R₂₁₁ and R₂₁₂ are independently selected from halogen, hydrogen, CN and NO₂ ;

R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, --S(O)_(k) CF₃, and --SF₅ ; and

h and k are independently selected from 0, 1, and 2.

A preferred group of compounds of formula (XX) is that wherein the ring which is formed by R₂₀₇ and R₂₀₈ is interrupted by one or more heteroatoms, more preferably one oxygen atom.

The compounds of formula (XX) of the present invention preferably have one or more of the following features:

R₂₀₁ is cyano;

R₂₀₃ is halomethyl, preferably CF₃ ;

R₂₁₁ and R₂₁₂ are independently halogen;

X₁ is C--R₂₁₂ ;

R₂₁₃ is haloalkyl, haloalkoxy or --SF₅ ; or

h is 0 or 1, or 2, preferably 0 or 1.

A preferred class of compounds is that wherein R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆ R₂₀₇ R₂₀₈.

Another preferred class of compounds is that wherein R₂₀₄ is N(R₂₀₅)C(O)aryl.

Another preferred class of compounds is that wherein R₂₀₄ is N(R₂₀₅)C(O)OR₂₀₇.

Preferably R₂₀₅ is C₁ -C₄ alkyl, more preferably C₁ -C₂ alkyl, most preferably methyl.

Preferably R₂₀₆ is alkoxy, most preferably methoxy, ethoxy or propoxy.

Preferably R₂₀₇ and R₂₀₈ are both hydrogen.

Among the compounds which may be used in the invention some are new and hence in another aspect of the present invention there is provided a compound of formula (II): ##STR3## wherein: R₂₁ is cyano, alkyl, haloalkyl, acetyl, --C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂ ;

R₂₂ is S(O)_(m) R₂₃ ;

R₂₃ is alkyl or haloalkyl;

R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇) or --N═C(R₂₅)--N(R₂₇)--R₂₈ ;

R₂₅ represents hydrogen or alkyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy or --S(O)_(m) R₃₅ ;

R₂₆ and R₂₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₃₅ ; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₃₅ is alkyl or haloalkyl and m is zero, one or two;

X is selected from nitrogen and C--R₃₂ ;

R₂₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or --S(O)_(t) R₃₀ ;

R₃₀ is alkyl or haloalkyl;

R₃₁ and R₃₂ are independently selected from halogen, hydrogen, CN and NO₂ ;

R₃₃ is selected from halogen, haloalkyl, haloalkoxy, --S(O)_(r) CF₃, and --SF₅ ;

m and r are independently selected from 0, 1, and 2; and t is 0 or 2; with the exclusion of the compound wherein R₂₁ is cyano; R₂₂ is --SCF₂ CH₃ ; R₂₅ is hydrogen; X is C--R₃₂ ; R₂₆ and R₂₇ are methyl; R₃₁ and R₃₂ are chlorine; and R₃₃ is trifluoromethyl; and veterinarily acceptable salts thereof.

A further class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano or methyl;

R₂₂ is S(O)_(m) R₂₃ ;

R₂₃ is haloalkyl;

R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ and R₂₇ are hydrogen or unsubstituted or substituted alkyl;

R₂₆ is haloalkyl;

X is selected from nitrogen and C--R₃₂ ;

R₃₁ and R₃₂ are independently selected from halogen, hydrogen, CN and NO₂ ;

R₃₃ is selected from halogen, haloalkyl, haloalkoxy, --S(O)_(r) CF₃, and --SF₅ ;

m and r are independently selected from 0, 1, and 2; with the exclusion of the compound wherein R₂₁ is cyano; R₂₂ is --SCF₂ CH₃ ; R₂₅ is hydrogen; X is C--R₃₂ ; R₂₆ and R₂₇ are methyl; R₃₁ and R₃₂ are chlorine; and R₃₃ is trifluoromethyl.

A preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m) R₂₃ ;

R₂₃ is halomethyl;

R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ is hydrogen or alkyl;

R₂₆ and R₂₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two;

X is selected from nitrogen and C--R₃₂ ;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is selected from haloalkyl, haloalkoxy and --SF₅ ;

m is selected from 0, 1, and 2.

A further preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m) CF₃ ;

R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇); or --N═C(R₂₅)--N(R₂₇)--R₂₈ ;

R₂₅ is hydrogen or methyl;

R₂₆ and R₂₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two;

R₂₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or --S(O)_(t) R₃₀ ;

X is selected from nitrogen and C--R₃₂ ;

R₃₀ is alkyl or haloalkyl;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is CF₃ or --SF₅ ; and

m is 0, 1 or 2; and t is 0 or 2.

A more preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m) CF₃ ;

R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ and R₂₇ each independently represent hydrogen or methyl;

R₂₆ represents hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₁₅ ; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two;

X is selected from nitrogen and C--R₃₂ ;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is CF₃ or --SF₅ ; and

m is 0, 1 or 2.

An especially preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m) CF₃ ;

R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ and R₂₇ each represent a hydrogen atom;

R₂₆ is alkyl or (preferably) haloalkyl;

X is C--R₃₂ ;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is CF₃ or --SF₅ ; and

m is 0.

In another aspect of the present invention there is provided a compound of formula (XX) or a salt thereof as hereinbefore defined, provided that the compound is not 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(N-ethoxycarbonyl-N-methyl)amino-4-trifluoromethylthiopyrazole.

Most preferably, the following compounds of formulae (I) and (XX) are preferred according to the present invention as listed in Tables 1 to 13. The Compound Numbers are for identification purposes only. The following symbols are hereby defined: Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl; n-Bu means n-Butyl, and n-Pent means n-Pentyl; Cy means cyclopropyl.

                  TABLE 1                                                          ______________________________________                                         Compounds of formula (I) wherein R.sub.1  is cyano; R.sub.2  is SCF.sub.3      R.sub.11  is Cl, X is C--CL, R.sub.4  is --N═C(R.sub.5)ZR.sub.6, Z is      NR.sub.7, R.sub.7  is H,                                                       and R.sub.13  is CF.sub.3  or SF.sub.5.                                        Compound   Compound                                                            Number     Number                                                              R.sub.13 ═CF.sub.3                                                                    R.sub.13 ═SF.sub.5                                                                       R.sub.5 R.sub.6                                       ______________________________________                                         201-1      201-2         Me      Me                                            202-1      202-2         Me      Et                                            203-1      203-2         Me      n-Pr                                          204-1      204-2         Me      i-Pr                                          205-1      205-2         Me      n-Bu                                          206-1      206-2         H       H                                             207-1      207-2         H       Et                                            208-1      208-2         H       n-Pr                                          209-1      209-2         H       i-Pr                                          210-1      210-2         H       n-Bu                                          211-1      211-2         H       CH.sub.2 CF.sub.3                             212-1      212-2         H       (CH.sub.2).sub.2 CF.sub.3                     213-1      213-2         H       CH.sub.2 OMe                                  214-1      214-2         H       (CH.sub.2).sub.2 OCF.sub.3                    215-1      215-2         Me      CH.sub.2 CF.sub.3                             216-1      216-2         Me      (CH.sub.2).sub.2 CF.sub.3                     217-1      217-2         Me      (CH.sub.2).sub.2 OMe                          218-1      218-2         Me      (CH.sub.2).sub.2 NMe.sub.2                    ______________________________________                                    

                  TABLE 2                                                          ______________________________________                                         Compounds of formula (I) wherein R.sub.1  is cyano; R.sub.11  is Cl;           R.sub.4  is                                                                    --N═C(R.sub.5)ZR.sub.6  and Z is NR7.                                      Cmpd                                                                           No.    R5       R6     R7        X    R13                                      ______________________________________                                         219    SCF3     H      CH3       CH3  C--Cl CF3                                220    SO2CF3   H      CH3       CH3  C--Cl CF3                                221    SCF3     H      CH2CN     H    C--Cl CF3                                222    SCF3     H      CH3       H    C--Cl CF3                                223    SOCF3    H      CH2Ph     H    C--Cl CF3                                224    SCF3     H      CH2Ph     H    C--Cl CF3                                225    SOCF3    H      CH3       H    C--Cl CF3                                226    SOCF3    H      CH3       H    C--Cl CF3                                227    SOCF3    H      CH2CF3    H    C--Cl CF3                                228    SO2CF3   H      2-propynyl                                                                               H    C--Cl CF3                                229    SO2CF3   H      CH2Ph     H    C--Cl CF3                                230    SO2CF3   H      CH2CF3    H    C--Cl CF3                                231    SOCF3    H      CH3       CH3  C--Cl CF3                                232    SCF3     H      CH2CF3    H    C--Cl CF3                                233    SCF3     H      CH2CF3    H    C--Cl CF3                                234    SCF3     H      2-propenyl                                                                               H    C--Cl CF3                                235    SCF3     H      2-propynyl                                                                               H    C--Cl CF3                                236    SOCF3    H      2-propynyl                                                                               H    C--Cl CF3                                237    SCF3     H      CH2OEt    H    N     CF3                                238    SCF3     H      CH2OCH2CF3                                                                               CH3  C--Cl CF3                                239    SO2CF3   H      CH2CF3    CH3  C--Cl SF5                                240    SCF3     H      CH2CF3    H    N     SF5                                241    SOCF3    H      CH2CH2CF3 H    C--Cl CF3                                242    SO2CF3   H      (CH2)3CF3 H    C--Cl CF3                                243    SCF3     H      (CH2)2N(CH3)2                                                                            H    C--Cl CF3                                244    SO2CF3   CH3    CH2(4-Cl Ph)                                                                             H    C--Cl CF3                                245    SCF3     H      CH2SO2CF3 H    C--Cl CF3                                246    SCF3     H      CH2(4-pyridyl)                                                                           H    C--Cl CF3                                247    SCF3     H      CH2(3-NO2 Ph)                                                                            H    C--Cl CF3                                248    SCF3     H      CH2CH2SCH3                                                                               H    C--Cl CF3                                249    SOCF3    H      CH2CF3    CH3  C--Cl CF3                                ______________________________________                                    

Note: Compounds 225 and 226 are regioisomers of the same molecular formula. In one, R₅ is H and R₆ is methyl; and in the other, R₅ is methyl and R₆ is H, but they cannot be distinguished.

Also note: Compound number 232 is the acetate salt, and compound number 233 is the citrate salt.

                  TABLE 3                                                          ______________________________________                                         Compounds of formula (I) wherein R.sub.1  is cyano; R.sub.11  is Cl;           and R.sub.4  is --N═C(R.sub.5)-N(R.sub.7)-R.sub.8.                         Cmpd                                                                           No.    R2       R5      R8     R7    X     R13                                 ______________________________________                                         250    SCF3     H       Oet    H     C--Cl CF3                                 251    SCF3     H       NHCH3  H     C--Cl CF3                                 252    SCF3     H       NHCH3  CH3   C--Cl CF3                                 253    SCF3     H       OCH2CF3                                                                               H     C--Cl CF3                                 254    SCF3     H       N(CH3)2                                                                               H     N     SF5                                 255    SCF3     H       NH2    H     C--Cl CF3                                 256    SCF3     H       S-nPr  H     C--Cl CF3                                 257    SO2CF3   Et      S-nPr  H     C--Cl SF5                                 258    SCF3     H       SO2CH3 H     C--Cl CF3                                 ______________________________________                                    

The following compounds of formula (XX) are preferred according to the present invention as listed in Tables 4-12.

                  TABLE 4                                                          ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.202  is           SCF.sub.3 ; R.sub.204  is N(R.sub.205)C(O)CR.sub.206 R.sub.207 R.sub.208       ; R.sub.207  and                                                               R.sub.208  ═H; R.sub.211  is Cl, X.sub.1  is C--Cl, and R.sub.213          is                                                                             CF.sub.3  or SF.sub.5.                                                         Compound    Compound                                                           Number      Number                                                             (R.sub.213 ═CF.sub.3)                                                                  (R.sub.213 ═SF.sub.5)                                                                 R.sub.205  R.sub.206                                    ______________________________________                                         1-1         1-2        Me         H                                            2-1         2-2        Me         OMe                                          3-1         3-2        Me         OEt                                          4-1         4-2        Me         O-i-Pr                                       5-1         5-2        Me         O-n-Bu                                       6-1         6-2        Et         H                                            7-1         7-2        Et         OMe                                          8-1         8-2        Et         OEt                                          9-1         9-2        Et         O-i-Pr                                       10-1        10-2       Et         O-n-Bu                                       11-1        11-2       n-Pr       H                                            12-1        12-2       n-Pr       OMe                                          13-1        13-2       n-Pr       OEt                                          14-1        14-2       n-Pr       O-i-Pr                                       15-1        15-2       n-Pr       O-n-Bu                                       16-1        16-2       i-Pr       H                                            17-1        17-2       i-Pr       OMe                                          18-1        18-2       i-Pr       OEt                                          19-1        19-2       i-Pr       O-i-Pr                                       20-1        20-2       i-Pr       O-n-Bu                                       21-1        21-2       n-Bu       H                                            22-1        22-2       n-Bu       OMe                                          23-1        23-2       n-Bu       OEt                                          24-1        24-2       n-Bu       O-i-Pr                                       25-1        25-2       n-Bu       O-n-Bu                                       26-1        26-2       CH.sub.2 Cy                                                                               H                                            27-1        27-2       CH.sub.2 Cy                                                                               OMe                                          28-1        28-2       CH.sub.2 Cy                                                                               OEt                                          29-1        29-2       CH.sub.2 Cy                                                                               O-i-Pr                                       30-1        30-2       CH.sub.2 Cy                                                                               O-n-Bu                                       31-1        31-2       CH.sub.2 CCH                                                                              H                                            32-1        32-2       CH.sub.2 CCH                                                                              OMe                                          33-1        33-2       CH.sub.2 CCH                                                                              OEt                                          34-1        34-2       CH.sub.2 CCH                                                                              O-i-Pr                                       35-1        35-2       CH.sub.2 CCH                                                                              O-n-Bu                                       36-1        36-2       Me         OAc                                          37-1        37-2       Me         CH.sub.2 OMe                                 38-1        38-2       Me         CH.sub.2 OEt                                 39-1        39-2       Me         O-i-Pr                                       40-1        40-2       Me         O-n-Bu                                       41-1        41-2       Me         OCH.sub.2 CF.sub.3                           ______________________________________                                    

                  TABLE 5                                                          ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.202  is           S(O)CF.sub.3 ; R.sub.204  is N(R.sub.205)C(O)CR.sub.206 R.sub.207              R.sub.208 ; R.sub.207  and                                                     R.sub.208  ═H; R.sub.211  is Cl, X.sub.1  is C--Cl, and R.sub.213          is                                                                             CF.sub.3  or SF.sub.5.                                                         Compound    Compound                                                           Number      Number                                                             (R.sub.213 ═CF.sub.3)                                                                  (R.sub.213 ═SF.sub.5)                                                                 R.sub.205  R.sub.206                                    ______________________________________                                         1-3         1-4        Me         H                                            2-3         2-4        Me         OMe                                          3-3         3-4        Me         OEt                                          4-3         4-4        Me         O-i-Pr                                       5-3         5-4        Me         O-n-Bu                                       6-3         6-4        Et         H                                            7-3         7-4        Et         OMe                                          8-3         8-4        Et         OEt                                          9-3         9-4        Et         O-i-Pr                                       10-3        10-4       Et         O-n-Bu                                       11-3        11-4       n-Pr       H                                            12-3        12-4       n-Pr       OMe                                          13-3        13-4       n-Pr       OEt                                          14-3        14-4       n-Pr       O-i-Pr                                       15-3        15-4       n-Pr       O-n-Bu                                       16-3        16-4       i-Pr       H                                            17-3        17-4       i-Pr       OMe                                          18-3        18-4       i-Pr       OEt                                          19-3        19-4       i-Pr       O-i-Pr                                       20-3        20-4       i-Pr       O-n-Bu                                       21-3        21-4       n-Bu       H                                            22-3        22-4       n-Bu       OMe                                          23-3        23-4       n-Bu       OEt                                          24-3        24-4       n-Bu       O-i-Pr                                       25-3        25-4       n-Bu       O-n-Bu                                       26-3        26-4       CH.sub.2 Cy                                                                               H                                            27-3        27-4       CH.sub.2 Cy                                                                               OMe                                          28-3        28-4       CH.sub.2 Cy                                                                               OEt                                          29-3        29-4       CH.sub.2 Cy                                                                               O-i-Pr                                       30-3        30-4       CH.sub.2 Cy                                                                               O-n-Bu                                       31-3        31-4       CH.sub.2 CCH                                                                              H                                            32-3        32-4       CH.sub.2 CCH                                                                              OMe                                          33-3        33-4       CH.sub.2 CCH                                                                              OEt                                          34-3        34-4       CH.sub.2 CCH                                                                              O-i-Pr                                       35-3        35-4       CH.sub.2 2CCH                                                                             O-n-Bu                                       36-3        36-4       Me         OAc                                          37-3        37-4       Me         CH.sub.2 OMe                                 38-3        38-4       Me         CH.sub.2 OEt                                 39-3        39-4       Me         O-i-Pr                                       40-3        40-4       Me         O-n-Bu                                       41-3        41-4       Me         OCH.sub.2 CF.sub.3                           ______________________________________                                          Compound 33 was separated into its enantiomers R33 and S33               

                  TABLE 6                                                          ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.202  is           S(O)CF.sub.3 ; R.sub.204  is N(R.sub.205)C(O)CR.sub.206 R.sub.207              R.sub.208 ; R.sub.207  and                                                     R.sub.208  ═H; R.sub.211  is Cl, X.sub.1  is C--Cl, and R.sub.213          is                                                                             CF.sub.3  or SF.sub.5.                                                         Compound    Compound                                                           Number      Number                                                             (R.sub.213 ═CF.sub.3)                                                                  (R.sub.213 ═SF.sub.5)                                                                 R.sub.205  R.sub.206                                    ______________________________________                                         1-5         1-6        Me         H                                            2-5         2-6        Me         OMe                                          3-5         3-6        Me         OEt                                          4-5         4-6        Me         O-i-Pr                                       5-5         5-6        Me         O-n-Bu                                       6-5         6-6        Et         H                                            7-5         7-6        Et         OMe                                          8-5         8-6        Et         OEt                                          9-5         9-6        Et         O-i-Pr                                       10-5        10-6       Et         O-n-Bu                                       11-5        11-6       n-Pr       H                                            12-5        12-6       n-Pr       OMe                                          13-5        13-6       n-Pr       OEt                                          14-5        14-6       n-Pr       O-i-Pr                                       15-5        15-6       n-Pr       O-n-Bu                                       16-5        16-6       i-Pr       H                                            17-5        17-6       i-Pr       OMe                                          18-5        18-6       i-Pr       OEt                                          19-5        19-6       i-Pr       O-i-Pr                                       20-5        20-6       i-Pr       O-n-Bu                                       21-5        21-6       n-Bu       H                                            22-5        22-6       n-Bu       OMe                                          23-5        23-6       n-Bu       OEt                                          24-5        24-6       n-Bu       O-i-Pr                                       25-5        25-6       n-Bu       O-n-Bu                                       26-5        26-6       CH.sub.2 Cy                                                                               H                                            27-5        27-6       CH.sub.2 Cy                                                                               OMe                                          28-5        28-6       CH.sub.2 Cy                                                                               OEt                                          29-5        29-6       CH.sub.2 Cy                                                                               O-i-Pr                                       30-5        30-6       CH.sub.2 Cy                                                                               O-n-Bu                                       31-5        31-6       CH.sub.2 CCH                                                                              H                                            32-5        32-6       CH.sub.2 CCH                                                                              OMe                                          33-5        33-6       CH.sub.2 CCH                                                                              OEt                                          34-5        34-6       CH.sub.2 CCH                                                                              O-i-Pr                                       35-5        35-6       CH.sub.2 CCH                                                                              O-n-Bu                                       36-5        36-6       Me         OAc                                          37-5        37-6       Me         CH.sub.2 OMe                                 38-5        38-6       Me         CH.sub.2 OEt                                 39-5        39-6       Me         O-i-Pr                                       40-5        40-6       Me         O-n-Bu                                       41-5        41-6       Me         OCH.sub.2 CF.sub.3                           ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.202  is           SCF.sub.3 ; R.sub.204  is N(R.sub.205)C(O)CR.sub.206 R.sub.207 R.sub.208       ; R.sub.211  is Cl;                                                            X.sub.1  is C--Cl; and R.sub.213  is CF.sub.3  or SF.sub.5 --.                 Compound Compound                                                              Number   Number                                                                (R.sub.213 ═CF.sub.3)                                                               (R.sub.213 ═SF.sub.5)                                                                R.sub.205                                                                               R.sub.206                                                                           R.sub.207, R.sub.208                          ______________________________________                                         1-7      1-8       Me       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              2-7      2-8       Et       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              3-7      3-8       i-Pr     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              4-7      4-8       n-Pr     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              5-7      5-8       n-Bu     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              6-7      6-8       Cy       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              7-7      7-8       CH.sub.2 Cy                                                                             H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              ______________________________________                                          Compound 17 was also separated into its enantiomers, called (R)17 and          (S)17.                                                                   

                  TABLE 8                                                          ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.202  is           S(O)CF.sub.3 ; R.sub.204  is N(R.sub.205)C(O)CR.sub.206 R.sub.207              R.sub.208 ; R.sub.211  is Cl,                                                  X.sub.1  is C--Cl; and R.sub.213  is CF.sub.3  or SF.sub.5.                    Compound Compound                                                              Number   Number                                                                (R.sub.213 ═CF.sub.3)                                                               (R.sub.213 ═SF.sub.5)                                                                R.sub.205                                                                               R.sub.206                                                                           R.sub.207, R.sub.208                          ______________________________________                                         1-9      1-10      Me       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              2-9      2-10      Et       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              3-9      3-10      i-Pr     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              4-9      4-10      n-Pr     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              5-9      5-10      n-Bu     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              6-9      6-10      CH.sub.2 Cy                                                                             H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              7-9      7-10      Cy       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              ______________________________________                                          Compound 19 was separated into its diastereomers, (R, R)19, (S, R)19, (S,      S)19, (R, S)19. The first designation of absolute configuration refers to      the configuration of the sulfoxide moiety, the second to the chiral            carbon.                                                                  

                  TABLE 9                                                          ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.202  is           S(O)CF.sub.3 ; R.sub.204  is N(R.sub.205)C(O)CR.sub.206 R.sub.207              R.sub.208 ; R.sub.211  is Cl;                                                  X.sub.1  is C--Cl; and R.sub.213  is CF.sub.3  or SF.sub.5 --.                 Compound Compound                                                              Number   Number                                                                (R.sub.213 ═CF.sub.3)                                                               (R.sub.213 ═SF.sub.5)                                                                R.sub.205                                                                               R.sub.206                                                                           R.sub.207, R.sub.208                          ______________________________________                                         1-11     1-12A     Me       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              2-11     2-12A     Et       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              3-11     3-12A     i-Pr     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              4-11     4-12A     n-Pr     H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              5-11     5-12A     n-Bu     H    --CH.sub.2 CH.sub.2 CH.sub.2 Q-               6-11     6-12A     Cy       H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              7-11     7-12A     CH.sub.2 Cy                                                                             H    --CH.sub.2 CH.sub.2 CH.sub.2 O--              ______________________________________                                          Compound 111 was also separated into its diastereomers, (R)111 and (S)111

                  TABLE 10                                                         ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.204 is            N(R.sub.205)C(O)CR.sub.206 R.sub.207 R.sub.208 ; R.sub.207  and R.sub.208       are H;                                                                        R.sub.211  is Cl, X.sub.1  is C--Cl; and R.sub.213  is CF.sub.3  or            SF.sub.5.                                                                      Compound      Compound                                                         Number        Number                                                           (R.sub.213 ═CF.sub.3)                                                                    (R.sub.213 ═SF.sub.5)                                                                R.sub.205  R.sub.206                                   ______________________________________                                         R.sub.202 ═SCF.sub.3                                                       1-12          1-13      Cy         H                                           2-12          2-13      Cy         OMe                                         3-12          3-13      Cy         OEt                                         4-12          4-13      Cy         i-O-Pr                                      5-12          5-13      Cy         O-n-Bu                                      R.sub.202 ═S(O)CF.sub.3                                                    6-12          6-13      Cy         H                                           7-12          7-13      Cy         OMe                                         8-12          8-13      Cy         OEt                                         9-12          9-13      Cy         O-i-Pr                                      10-12         10-13     Cy         O-n-Bu                                      R.sub.202 ═S(O).sub.2 CF.sub.3                                             11-12         11-13     Cy         H                                           12-12         12-13     Cy         OMe                                         13-12         13-13     Cy         OEt                                         14-12         14-13     Cy         O-i-Pr                                      15-12         15-13     Cy         O-n-Bu                                      ______________________________________                                    

                  TABLE 11                                                         ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.204  is           --N(R.sub.205)C(O)OR.sub.207 ; R.sub.211  is Cl; X.sub.1  is C--Cl, and        R.sub.213  is CF.sub.3                                                         or SF.sub.5.                                                                   Compound       Compound                                                        Number         Number                                                          (R.sub.213 ═CF.sub.3)                                                                     (R.sub.213 ═SF.sub.5)                                                                  R.sub.205                                                                               R.sub.207                                  ______________________________________                                         R.sub.202  is SCF.sub.3                                                        67-1           67-2        Me       Me                                         68-1           68-2        Me       Et                                         69-1           69-2        Me       i-Pr                                       70-1           70-2        Me       n-Pr                                       71-1           71-2        Et       Me                                         72-1           72-2        Et       Et                                         73-1           73-2        Et       i-Pr                                       74-1           74-2        Et       n-Pr                                       75-1           75-2        n-Pr     Me                                         76-1           76-2        n-Pr     Et                                         77-1           77-2        n-Pr     i-Pr                                       78-1           78-2        n-Pr     n-Pr                                       79-1           79-2        i-Pr     Me                                         80-1           80-2        i-Pr     Et                                         81-1           81-2        i-Pr     i-Pr                                       82-1           82-2        i-Pr     n-Pr                                       R.sub.202  is S(O)CF.sub.3                                                     83-1           83-2        Me       Me                                         84-1           84-2        Me       Et                                         85-1           85-2        Me       i-Pr                                       86-1           86-2        Me       n-Pr                                       87-1           87-2        Et       Me                                         88-1           88-2        Et       Et                                         89-1           89-2        Et       i-Pr                                       90-1           90-2        Et       n-Pr                                       91-1           91-2        n-Pr     Me                                         92-1           92-2        n-Pr     Et                                         93-1           93-2        n-Pr     i-Pr                                       94-1           94-2        n-Pr     n-Pr                                       95-1           95-2        i-Pr     Me                                         96-1           96-2        i-Pr     Et                                         97-1           97-2        i-Pr     i-Pr                                       98-1           98-2        i-Pr     n-Pr                                       R.sub.202  is S(O).sub.2 CF.sub.3                                              99-1           99-2        Me       Me                                         100-1          100-2       Me       Et                                         101-1          101-2       Me       i-Pr                                       102-1          102-2       Me       n-Pr                                       103-1          103-2       Et       Me                                         104-1          104-2       Et       Et                                         105-1          105-2       Et       i-Pr                                       106-1          106-2       Et       n-Pr                                       107-1          107-2       n-Pr     Me                                         108-1          108-2       n-Pr     Et                                         109-1          109-2       n-Pr     i-Pr                                       110-1          100-2       n-Pr     n-Pr                                       111-1          111-2       i-Pr     Me                                         112-1          112-2       i-Pr     Et                                         113-1          113-2       i-Pr     i-Pr                                       114-1          114-2       i-Pr     n-Pr                                       ______________________________________                                    

                  TABLE 12                                                         ______________________________________                                         Compounds of formula (XX) wherein R.sub.201  is cyano; R.sub.202  is           S(O).sub.h CF.sub.3 ; R.sub.204  is N(R.sub.205)C(O)CR.sub.206 R.sub.207       R.sub.208 ; R.sub.211  is Cl;                                                  X.sub.1  is C--Cl, and R.sub.213  is CF.sub.3  or SF.sub.5.                    Com-  Com-                                                                     pound pound                                                                    Number                                                                               Number                                                                   (R.sub.213 ═                                                                     (R.sub.213 ═                                                         CF.sub.3)                                                                            SF.sub.5)                                                                              h     R.sub.205                                                                           R.sub.201                                                                               R.sub.207                                                                              R.sub.208                            ______________________________________                                         115-1 115-2   0     Me   H        Me      Me                                   116-1 116-2   0     Me   OEt      H       Me                                   117-1 117-2   0     Me   H        --CH.sub.2 CH.sub.2 --                       118-1 118-2   0     Me   OMe      H       Me                                   119-1 119-2   0     Me   OEt      Me      Me                                   120-1 120-2   2     Me   OCH.sub.2 CH.sub.2 OMe                                                                  H       H                                    121-1 121-2   0     Me   H        --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                          O--                                          122-1 122-2   1     Me   OEt      H       Me                                   123-1 123-2   0     Me   H        H       Me                                   124-1 124-2   0     Me   H        H       Et                                   ______________________________________                                    

                  TABLE 13                                                         ______________________________________                                         Compounds of formula (XX) wherein R.sub.201 is cyano; R.sub.202 is             S(O).sub.h CF.sub.3 ; R.sub.204 is N(R.sub.205)C(O)aryl; R.sub.205 is          CH.sub.3 ; R.sub.211 is Cl;                                                    X.sub.1 is C--Cl, and R.sub.213 is CF.sub.3 or SF.sub.5. Within this           table the                                                                      following symbols are defined: Ph means phenyl; Fu means furyl;                Th means the thiophene radical, i.e. thienyl; Pyr means pyridyl.               Compound       Compound                                                        Number         Number                                                          (R.sub.213 = CF.sub.3)                                                                        (R.sub.213 = SF.sub.5)                                                                   Aryl                                                  ______________________________________                                         R.sub.202 is SCF.sub.3                                                         125-1          125-2     Ph                                                    126-1          126-2     4-Ome--Ph                                             127-1          127-2     4-CF.sub.3 --Ph                                       128-1          128-2     2-Th                                                  129-1          129-2     3-Th                                                  130-1          130-2     2-Fu                                                  131-1          131-2     3-Fu                                                  132-1          132-2     2-Pyr                                                 133-1          133-2     3-Pyr                                                 134-1          134-2     4-Pyr                                                 135-1          135-2     6-Cl-2-Pyr                                            136-1          136-2     6-CF.sub.3 -2-Pyr                                     137-1          137-2     5-Cl-2-Fu                                             138-1          138-2     5-CF.sub.3 -2-Fu                                      139-1          139-2     5-OMe-2-Th                                            140-1          140-2     5-CF.sub.3 -2-Th                                      R.sub.202 is S(O)CF.sub.3                                                      125-3          125-4     Ph                                                    126-3          126-4     4-OMe--Ph                                             127-3          127-4     4-CF.sub.3 --Ph                                       128-3          128-4     2-Th                                                  129-3          129-4     3-Th                                                  130-3          130-4     2-Fu                                                  131-3          131-4     3-Fu                                                  132-3          132-4     2-Pyr                                                 133-3          133-4     3-Pyr                                                 134-3          134-4     4-Pyr                                                 135-3          135-4     6-Cl-2-Pyr                                            136-3          136-4     6-CF.sub.3 -2-Pyr                                     137-3          137-4     5-Cl-2-Fu                                             138-3          138-4     5-CF.sub.3 -2-Fu                                      139-3          139-4     5-OMe-2-Th                                            140-3          140-4     5-CF.sub.3 -2-Th                                      R.sub.202 is S(O).sub.2 CF.sub.3                                               125-5          125-6     Ph                                                    126-5          126-6     4-OMe--Ph                                             127-5          127-6     4-CF.sub.3 --Ph                                       128-5          128-6     2-Th                                                  129-5          129-6     3-Th                                                  130-5          130-6     2-Fu                                                  131-5          131-6     3-Fu                                                  132-5          132-6     2-Pyr                                                 133-5          133-6     3-Pyr                                                 134-5          134-6     4-Pyr                                                 135-5          135-6     6-Cl-2-Pyr                                            136-5          136-6     6-CF.sub.3 -2-Pyr                                     137-5          137-6     5-Cl-2-Fu                                             138-5          138-6     5-CF.sub.3 -2-Fu                                      139-5          139-6     5-OMe-2-Th                                            140-5          140-6     5-CF.sub.3 -2-Th                                      ______________________________________                                    

The present invention also relates to a composition comprising a parasiticidally effective, substantially non-emetic amount of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof and an acceptable carrier. Acceptable carriers for the use of the compounds are generally known to the skilled addressee concerned with pest control in animals, particularly domestic animals, most preferably dogs or cats.

The compositions which can be used in the invention can comprise generally from about 0.001 to 95% of the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof. The remainder of the composition up to 100% comprises a carrier as well as generally various additives. In this specification and the accompanying claims, percentages are by weight.

The diluted liquid formulations generally comprise from about 0.001 to about 3% of compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof, preferably from about 0.1 to about 0.5%.

Solid formulations generally comprise from about 0.1 to about 8% of compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof, preferably from about 0.5 to about 1.5%.

Compositions for oral administration comprise one or more of the compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof in association with veterinarily acceptable carriers or coatings and include, for example, tablets, pills, capsules, gels, drenches, medicated feeds, medicated drinking water, medicated dietary supplements, slow-release boluses or other slow-release devices intended to be retained within the gastro-intestinal tract. Any of these may incorporate the active ingredients contained within micro-capsules or coated with acid-labile or alkali-labile or other pharmaceutically acceptable enteric coatings. Feed premixes or concentrated containing compounds of the present invention for use in preparation of medicated diets, drinking water or other materials for consumption by animals may also be used. In a highly preferred embodiment, the compositions are administered postprandially, preferably form just after a meal to 2 hours after the meal.

In a highly preferred embodiment, there is provided a product which is readily chewed by the animal and which product does generally not allow human contamination when the product is provided to the animal by hand.

The compounds of general formula (I) or salts thereof or compounds of formula (XX) or slats thereof may be administered before, during or after meals. The compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof may by mixed with a carrier and/or a foodstuff.

According to the present invention the compound of formula (I) or a salt thereof or a compound of formula (XX) or a slat thereof is administered orally in a dose to the animal in a dose range generally from 0.1 to 500 mg/kg of the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof per kilogram of animal body weight (mg/kg). preferably form 1 to 100 mg/kg, more preferably from 1 to 50 mg/kg, even more preferably from 2 to 25 mg//kg, most preferably from 3 to 15 mg/kg.

According to the present invention, the frequency of treatment of the animal, preferably the domestic animal to be treated by the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof, is generally from about once per week to about once per year, preferably from about once every two weeks to about once every six months, more preferably from about once every two weeks to once every three months, and most preferably from abut once every two weeks to about once every six weeks.

Generally the animal to be treated is a domestic animal, preferably a domestic companion animal. More preferably the animal to be treated is a dog and/or a cat.

The compounds of the invention may be administered most advantageously with another parasiticidally effective material, such as an endoparasiticide, and/or an ectoparasiticide, and/or an endectiparasiticide. For example, such compounds include macrocyclic lactones such as avermectins or milbemycins e.g., ivermectin; pyratel (generally administered as pyrantel pamoate) or an insect growth regulator such as lufenuron or methoprene.

By the term "parasites" as used in the specification and claims is meant endoparasites and ectoparasites of warm-blooded animals, particularly ectoparasites. Preferably, fleas and/or ticks are controlled by the method of the present invention.

Illustrative of specific parasites of various host animals which may be controlled by the method of this invention include arthropods such as:

Mites: Mesostigmata spp. e.g. mesostigmatids such as the chicken mite, Dermanyssus gallinae; itch or scab mites such as Sacroptidae spp. for example Sarcoptes scabiei; mange mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis; chiggers e.g. Trombiculidae spp. for example the north american chigger, Trombicula alfreddugesi;

Ticks: e.g., soft-bodies ticks including Argaisidae spp. for example Argas spp, and Ornithodoros spp; hard-bodied ticks including Ixodidae spp., for example Rhipicephalus sanguineus, and Boophilus spp.;

Lice: sucking lice, e.g., Menopon spp. and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.;

Fleas: e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. such as human flea (Pulex irritans);

True bugs: e.g., Cimicidae or including the common bed bug (Cimex lectularius); Triatominae spp, including triatomid bugs also known as kissing bugs; for example Rhodnius prolixus and Triatoma spp.;

bloodsucking adult flies: (e.g., horn fly [Haematobia irritans], horse fly [Tabanus spp.], stable fly [Stomoxys calcitrans], black fly [Simulium spp.], deer fly [Chrysops spp.], [louse fly ] [Melophagus ovinus], tsetse fly [Glossina spp.], mosquitoes [Culex spp., Anopheles spp., and Aedes spp.]); and

parasitic fly maggots; (e.g., bot fly [Oestrus ovis and Cuterebra spp.], blow fly [Phaenicia spp.], screwworm [Cochliomyia hominivorax], cattle grub [Hypoderma spp.], fleeceworm).

The present invention also relates to a use of a compound of formula (I) or a slat thereof or a compound of formula (XX) or a salt thereof hereinbefore described as a therapeutic agent, preferably for animals, more preferably for domestic animals.

The veterinary composition may be sterile or non-sterial. It may be a liquid (e.g. aqueous) oar solid (e.g., dry ) composition, in particular a freeze-dried composition, which, by addition of water or another liquid, orally effective solutions may be prepared.

The present invention also relates to a use of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof as hereinbefore defined for the manufacture of a veterinary composition for the control of parasites in or on an animal.

The present invention also relates to a method of cleaning animals in good health comprising the application to the animal of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof as hereinbefore defined to the animal.

The method of cleaning an animal is not a method of treatment by therapy of the animal body per se, because

(a) the animal is in good health and required no substantial treatment to correct a deficiency of health;

(b) the cleaning of the animal is not intended to be done by veterinary personnel, but by persons interested in the cleaning of the animal; and

(c) the purpose of such cleaning is to avoid unpleasant conditions for humans and the environment in which humans inhabit so as to not infest the said humans with arthropods carried by the animal.

By "carrier" is meant an organic or inorganic material, which can be natural or synthetic, and which is associated with the compound and which facilitates its application to the animal. This carrier is thus generally inert and should be arthropocidally acceptable, The carrier can be solid (e.g., clay, silicates, silica, resins, wax) or liquid (e.g., water, alcohols, ketones, oil solvents, polar aprotic solvents). An example of an oil solvent is corn oil. An example of a polar aprotic solvent is dimethyl sulfoxide.

The compounds of formula (II) wherein R₂₁ R₂₂ R₂₄, R₃₁, R₃₃ and X are as defined above may be prepared from the compounds of formula (III): ##STR4## wherein R₂₁, R₂₂, R₃₁, R₃₃ and X are as defined above, using processes described in European Patent Publications 0511845 or 0659745, incorporated by reference herein and relied upon.

According to a feature of the present invention, compounds of formula (II) wherein R₂₁, R₂₂, R₃₁, R₃₃ and X are as define above and R₂₄ is -N═C(R₂₅)-NR₂₆ R₂₇ wherein R₂₅, R₂₆ R₂₇ are as defined above may be prepared by reacting a compound of formual (III) with a compound of formula (IV): ##STR5## wherein R₂₅,R₂₆ and R₂₇ are as defined above and R₁₀₀ is generally an alkyl group. The reaction is optionally conducted in the presence of a catalyst such as a mineral or organic acid (for example hydrochloric acid), a generally using form 1 to 100 equivalents of (IV), preferably using 1 to 10 equivalents of (IV), and is preferably conducted in an organic solvent such as tetrahydrofuran, toluene, or N,N-dimethylformamide, at a temperature of from 0° C. to 150° C. Additional adjuvants such as drying agents (e.g. magnesium sulfate, potassium carbonate, or molecular sieves) may also be advantageous to the reaction. Compounds of formula (IV) are known or may be prepared by known procedures.

According to a feature of the present invention, compounds of formula (II) wherein R₂₁, R₂₂, R₃₁, R₃₃ and X are as defined above and R₂₄ is -N═C(R₂₅)-NR₂₆ R₂₇ wherein R₂₅, R₂₆ and R₂₇ are as defined above, may be prepared by the reaction of a compound of formula (V): ##STR6## wherein R₂₁, R₂₂, R₂₅, R₃₁, R₃₃, X and R₁₀₀ are as defined above, with a compound of formula (VI): ##STR7## Wherein R₂₆ R₂₇ are as defined above. The reaction is generally conducted using the same conditions as used for the preparation of compounds of formula (II) by the reaction of compounds of formula (III) with compounds of formula (IV).

According to a feature of the present invention, compounds of formula (II) wherein R₂₄ is -N═C(R₂₅)-NR₂₇ R₂₈, and R₂₁, R₂₂, R₂₅, R₂₇,R₃₁, R₃₃ and X are as defined above, and R₂₈ is COR₃₄ wherein R₃₄ is as defined above, may be prepared by the reaction of the corresponding compounds of formula (II) wherein R₂₄ is -N═C(R₂₅)-NR₂₇ H with an acid chloride of formula (VII):

    R.sub.34 COCL                                              (VII)

wherein R₃₄ is as defined above, The reaction is generally performed in the presence of a base such as a trialkylamine, for example trimethylamine, in a solvent such as dichloromethane, at a temperature of from 0° C. to 50° C.

According to a feature of the present invention, compounds of formula (II) wherein R₂₄ is -N═C(R₂₅)-R₂₇ R₂₈, and R₂₁, R₂₂, R₂₅, R₂₇, R₃₁, R₃₃ and X are as defined above and R₂₈ is -S(O)_(t) R₃₀ may be prepared by the reaction of the corresponding compound of formula (II) wherein R₂₄ is -N═C(R₂₅)-NR₂₇ H with a sulfonyl chloride or a sulfenyl chloride of formula (VIII):

    R.sub.30 S(O).sub.t Cl                                     (VIII)

The reaction is generally performed in the presence of a weak base such as a trialkylamine for example triethylamine, or pyridine in a solvent such as dichloromethane, at a temperature of from 0° C. to 50° C.

Compounds of formula (VI), (VII) and (VIII) are known or may be prepared by known procedures.

Compounds of formula (III) and (V) may be generally prepared according to known processed, for example as described in International Patent Publications WO 87/03781, WO 93/06089, WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European Patent Publications 0295117, 0846686, and U.S. Pat. No. 5,232,940.

In another aspect of the present invention, compounds of formula (XX) wherein R₂₀₄ is -N(R₂₀₅)C(O)CR₂₀₆ R₂₀₇ R₂₀₈, N(R₂₀₅)C(O)aryl, or N(R₂₀₅)C(O)OR₂₀₇ are generally prepared from compounds of formula (XXI): ##STR8## by reaction with halides of formulae X₂ C(O)CR₂₀₆ R₂₀₇ R₂₀₈, X₂ C(O)aryl, or X₂ C(O)OR₂₀₇, respectively, wherein R₂₀₁, R₂₀₂, R₂₀₅, R₂₀₆, R₂₀₇, R₂₀₈, R₂₁₁ R₂₁₃, and X₁ are defined above and wherein X₂ is a halogen atom. The reaction is generally carried out in the presence of a base, generally using form 1 to 10 molar equivalents of the halide, and is preferably conducted in the presence of an organic solvent such as tetrahydrofuran, methylene chloride, at a temperature of from 0° C. to 150° C.

Compounds of formula (XXI) may be prepared from a compound of formula (XXII): ##STR9## by reaction with a compound of formula (XXIII);

    X.sub.2 R.sub.205                                          (XXIII)

wherein R₂₀₁, R₂₀₂, R₂₀₅, R₂₁₁, R₂₁₃, X₁ and X₂ are defined above. Compounds of formula (XXIII) are generally known in the art as alkylhalides or substituted alkylhalides. Compounds of formula (XXII) may be prepared by methods described in International Patent Publications WO 87/03781, WO 93/06089, WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European Patent Publications 0295117, 0659645, 0846686, and U.S. Pat. No. 5,232,940 or other methods known to the person skilled in the art.

Alternatively compounds of formula (XXI) may be prepared by reduction of compounds of formula (XXIV): ##STR10## wherein R₂₀₁, R₂₀₂, R₂₁₁, R₂₁₃ and X₁ are defined above. The reduction generally is effected by he use of a standard hydride ion donor, for example sodium borohydride or sodium cyanoborohydride. The reaction is generally effected in an polar solvent such as ethanol or methanol and generally using form 1 to 10 molar equivalents of the hydride, and is preferably conducted at temperature of from -100° C. to 150° C.

Compounds of formula (XXIV) may be prepared using methods described in EP 0295117, WO 97/22593 or other methods known to those skilled in the art.

In another aspect of the invention there are provided the compounds 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino4-trifluoromethylsufinylpyrazole and 3-cyano-1-(2,6dichloro-4-trifluoromethylpheny)-5-methylamino-4-trifluoromethylsulfinylpyrazole which are useful intermediates for the preparation of compounds for use according to the present invention.

Biological Example

Compounds 1-1, 2-1, 3-1, 4-1, 11-1, 13-1, 28-1, 31-1, 32-1, 36-1, 37-1, 38-1, 1-3, 2-3, 3-3, 4-3, 6-3, 41-3, 1-5, 2-5, 3-5, 6-5, 11-5, 27-5, 28-5, 1-7, 3-7, 5-7, 1-9, 1-11, 6-11, 7-11, 1-12, 11-12, 13-12, 67-1, 68-1, 69-1, 70-1, 72-1, 75-1, 76-1, 77-1, 78-1, 79-1, 80-1, 81-1, 82-1, 115-1, 116-1, 117-1, 118-1, 119-1, 120-1, 121-1, 122-1, 123-1, 124-1, 211-1, 219, 220, 221, 22, 223, 223, 225, 226, 227, 228, 229, 230, 231, 232, 233R3-3, S3-3R1-7, S1-7, (R,S)1-9, (R,R)1-9, (S,R)1-9, (S,S)1-9, S1-11, R1-11, 126-1, 127-1 and 130-1 were each formulated as a 30 mg/mL formulation in a 1:1 volume/volume solution of dimethyl sulfoxide and corn oil. Using this formulation, mixed breed dogs and cats were treated at a rate of 10 mg of the compound per kg (mg/kg) of body weight of the dog and 20 mg/kg of the at treated. The animals were fasted for at least 8 hours prior to treatment, fed half of the daily ration immediately prior to treatment, then allowed access to the remainder of the daily ration immediately following treatment.

All dogs were infested with cat fleas (Ctenocephalids felis) and with ticks (Rhipicephalus sanguineus) 1 day prior to administration of the compound. Cats were only infested with fleas. The initial flea and tick counts were performed 1 day after the administration of the compounds. At 7, 14, 21 and 28 days after treatment the dogs were re-infested with ticks and 8, 15, 22 and 29 days after treatment the dogs and cats were re-infested with fleas. At 1, 9, 16, 23 and 30 days after treatment the control of fleas and ticks in treated dogs and cats was determined versus a group on infested dogs and cats which received a placebo consisting of a 1:1 volume/volume solution of dimethyl sulfoxide and corn oil. To determine the efficacies of the compounds, the arthropods were combed from the animals and counted.

In the animals treated with the compounds above, there was substantially no emesis after 2, 8 and 24 hours. Generally long-term control of fleas and ticks was provided in dogs. In the cats treated, there was commercially acceptable control of fleas for at least one day post treatment.

The results of this example were superior to those obtained with compounds of the prior art, for example, fipronil.

The following non-limiting Synthesis Examples illustrate the preparation of compounds of formula (I) and the Reference Examples illustrate the preparation of intermediates used in their synthesis.

Synthesis Example 1

A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (1 g) in N,N-dimethylformamide dimethyl acetal was heated at 50° C. for 1 hour. Evaporation of solvents gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-N'-dimethylaminomethylideneamino-4-trifluoromethylthiopyrazole m.p. 141° C.

By proceeding in a similar manner the following compounds were also prepared:

3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-N'-dimethylaminomethylideneamino-4-trifluoromethylsulfonylpyrazole m.p. 209° C.; and

3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-N'-dimethylaminomethylideneamino-4-trifluoromethylsulfinylpyrazole m.p. 207° C.

Synthesis Example 2

A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylthiopyrazole (5 g) in ethanol was treated with benzylamine (11.4 ml), stirred overnight, evaporated and purified by reverse-phase column chromatography (C-18 stationary phase column, eluting with MeOH/water) to give 5-N'-benzylaminomethylideneamino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (1.18 g), m.p. 113° C.

By proceeding in a similar manner the compounds of formula (II) wherein R₂₁ is CN; R₂₄ is --N═CH-NHR₂₆ ; R₃₁ is Cl; X is C-Cl; and R₃₃ is CF₃ shown in Table 4 were also prepared.

                  TABLE 4                                                          ______________________________________                                         Compd No.   R22        R26         M.P. ° C.                            ______________________________________                                         21          SCF3       CH2CN       175                                         211-1       SCF3       CH2CF3      130                                         222         SCF3       CH3         173                                         223         SOCF3      CH2Ph       173                                         225         SOCF3      CH3         144                                         226         SOCF3      CH3         144                                         227         SOCF3      CH2CF3      175                                         228         SO2CF3     2-propynyl  149                                         229         SO2CF3     CH2Ph       182                                         230         SO2CF3     CH2CF3      183                                         209-1       SCF3       iPr                                                     207-1       SCF3       CH2CH3      141                                         ______________________________________                                    

Reference Example 1

A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (500 g) in triethyl orthoformate was treated with concentrated hydrochloric acid (10 ml) and heated at 50° C. After 8 hours the reaction mixture was evaporated to give a solid which was washed (heptane) and air-dried to give 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylthiopyrazole (217 g), m.p. 68° C.

By proceeding in a similar manner the following intermediates were also prepared:

3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole, m.p. 63° C.; and 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfonylpyrazole, m.p. 118° C.

Synthesis Example 3

3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (111.55 g, 0.247 moles), triethylamine (62.45 g, 0.618 moles), 4-dimethylaminopyridine (3 g, 0.0247 moles), and tetrahydrofuran (700 ml) was combined. The resulting solution was heated to 45° C. and ethoxyacetyl chloride (45.2 g, 0.37 mmol) was added dropwise over 10 min. After 1 h, the mixture was evaporated to a brown residue, which was dissolved in 500 ml of ethyl acetate and washed with 2×300 ml water. The organic phase was dried over magnesium sulfate, filtered, and evaporated to a brown oil. The oil was triturated with 1 L of hot cyclohexane. The resulting solids were collected by filtration and washed with 500 ml of hot cyclohexane, then air dried to afford compound 3--3 as a beige powder (116.7 g). Evaporation of the mother liquors afforded a second crop of compound 3--3 (8.4 g).

In a similar fashion or by modifications according to methods known to the skilled addressee, the following compounds were prepared. The compound numbers in the left column refer to the Tables cited above.

    ______________________________________                                                       Mass Spectral                                                    Compound      molecular ion + 1                                                Number        (M + 1)                                                          ______________________________________                                          1-1          477                                                               2-1          507                                                               3-1          521                                                               4-1          535                                                              11-1          505                                                              13-1          549                                                              28-1          537                                                              31-1          517                                                              32-1          531                                                              36-1          535                                                              37-1          521                                                              38-1          535                                                               1-3          593                                                               2-3          523                                                               3-3          537                                                               4-3          551                                                               6-3          491                                                              41-3          473                                                               1-5          509                                                               2-5          539                                                               3-5          553                                                               6-5          523                                                              11-5          537                                                              27-5          579                                                              28-5          593                                                               1-7          533                                                               3-7          561                                                               5-7          575                                                               1-9          549                                                               1-11         565                                                               6-11         591                                                               7-11         605                                                               1-12         535                                                               11-12        565                                                               13-12        579                                                              67-1          493                                                              68-1          507                                                              69-1          521                                                              70-1          521                                                              72-1          521                                                              75-1          521                                                              76-1          535                                                              77-1          549                                                              78-1          549                                                              79-1          521                                                              80-1          535                                                              81-1          549                                                              82-1          549                                                              115-1         505                                                              116-1         535                                                              117-1         503                                                              118-1         521                                                              119-1         549                                                              120-1         583                                                              121-1         547                                                              122-1         551                                                              123-1         491                                                              124-1         505                                                              126-1         507                                                              127-1         607                                                              130-1         529                                                              ______________________________________                                    

Reference Example 2

Step A: Preparation of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole.

A 12-L three-necked flask fitted with an overhead stirrer, heating mantle, water separator (e.g. Dean Stark trap) with condenser was placed under a nitrogen atmosphere and charged with 1.475 kg (3.37 moles) of fipronil and 6 L of triethyl orthoformate. The suspension was heated to reflux over 2.5 h, then at reflux for 3 h with collection and removal of the distillate. The mixture was cooled to room temperature, then evaporated under reduced pressure at a bath temperature of 60-80° C., then at 50° C. overnight. The resulting beige solid, 1.717 kg (95.8% by HPLC, 3.335 moles, 99% purity corrected yield) was used without further purification. (m.p. about 63° C.)

Step B: Preparation of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole.

A 50 L reactor was charged with 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole (1.645 g, 3.335 moles) and absolute ethanol (16 L) under nitrogen. The solution was cooled to 10° C., and sodium borohydride (266 g, 7.03 moles) was added slowly such that the temperature remained generally below 35° C. After 6.75 h, some additional sodium borohydride (25 g, 0.66 moles) was added and stirring was continued overnight. Acetic acid (1.3 L, 22.7 moles) was added to quench, followed by 16 L of water. The resulting precipitate was collected by filtration, washed with water, and air-dried. Recrystallization from methanol afforded 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (350 g) as an off-white solid. (m.p. about 227° C.)

While the invention has been described in terms of various preferred embodiments, the person skilled in the art will appreciate that various modifications, substitutions, omissions and changes can be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof. 

What is claimed is:
 1. A compound having the formula (II): ##STR11## wherein: R₂₁ is cyano;R₂₂ is S(O)_(m) R₂₃ ; R₂₃ is alkyl or haloalkyl; R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇); R₂₅ is hydrogen, alkyl, or alkyl substituted by one or more halogen, alkoxy, haloalkoxy or --S(O)_(m) R₃₅ ; R₂₆ and R₂₇ each independently are hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₃₅ ; or alkyl substituted by phenyl or pyridyl each of which ring is optionally substituted with one or more members selected from the group consisting of halogen, nitro and alkyl; with the proviso that at least one of R₂₆ and R₂₇ is alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₃₅, or at least one of R₂₆ and R₂₇ is alkyl substituted by phenyl or pyridyl each of which ring is optionally substituted with one or more members selected from the group consisting of halogen, nitro and alkyl; X is nitrogen or C-R₃₂ ; R₂₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or --S(O)_(t) R₃₀ ; R₃₀ is alkyl or haloalkyl; R₃₁ and R₃₂ are, independently, halogen, hydrogen, CN or NO₂ ; R₃₃ is halogen, haloalkyl, haloalkoxy, --S(O)_(r) CF₃, or --SF₅ ; R₃₅ is alkyl or haloalkyl; m and r are, independently, 0, 1 or 2; and t is 0 or 2; or a veterinarily acceptable salt thereof.
 2. A compound according to claim 1, wherein R₂₂ is SCF₃ ; R₃₁ is Cl; X is C-Cl; R₃₃ is CF₃ or SF₅ ; R₂₇ is H; R₂₅ is hydrogen or alkyl; and R₂₆ is alkyl substituted by halogen, alkoxy, haloalkoxy or dialkylamino.
 3. A compound according to claim 2, wherein R₂₅ is hydrogen or methyl.
 4. A compound according to claim 2, wherein R₂₆ is CH₂ CF₃, (CH₂)₂ CF₃, CH₂ OCH₃, (CH₂)₂ OCF₃, (CH₂)₂ OCH₃ or (CH₂)₂ N(CH₃)₂.
 5. A compound according to claim 4, wherein R₂₅ is hydrogen or methyl.
 6. The compound according to claim 5, wherein R₃₃ is CF₃, R₂₅ is hydrogen and R₂₆ is CH₂ CF₃.
 7. A compound according to claim 1, wherein R₂₂ is SCF₃, SO₂ CF₃ or SOCF₃ ; R₃₁ is Cl; X is C-Cl or N; R₃₃ is CF₃ or SF₅ ; R₂₅ is hydrogen or methyl; R₂₆ is CH₂ CN, benzyl, CH₂ CF₃, 2-propynyl, 2-propenyl, CH₂ OC₂ H₅, CH₂ OCH₂ CF₃, CH₂ CH₂ CF₃, (CH₂)₃ CF₃, (CH₂)₂ N(CH₃)₂, 4-chlorobenzyl, CH₂ SO₂ CF₃, (4-pyridyl)methyl, 3-nitrobenzyl or CH₂ CH₂ SCH₃ ; and R₂₇ is hydrogen or methyl.
 8. A compound according to claim 7, wherein R₂₅ is H, X is C-Cl and R₃₃ is CF₃.
 9. The compound according to claim 8 wherein:(a) R₂₂ is SCF₃, R₂₆ is CH₂ CN and R₂₇ is H; (b) R₂₂ is SOCF₃, R₂₆ is benzyl and R₂₇ is H; (c) R₂₂ is SCF₃, R₂₆ is benzyl and R₂₇ is H; (d) R₂₂ is SOCF₃, R₂₆ is CH₂ CF₃ and R₂₇ is H; (e) R₂₂ is SO₂ CF₃, R₂₆ is 2-propynyl and R₂₇ is H; (f) R₂₂ is SO₂ CF₃, R₂₆ is benzyl and R₂₇ is H; (g) R₂₂ is SO₂ CF₃, R₂₆ is CH₂ CF₃ and R₂₇ is H; or (h) R₂₂ is SCF₃, R₂₆ is CH₂ CF₃ and R₂₇ is H.
 10. A method of controlling parasites in or on an animal in need of such control, said method comprising orally administering to said animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole having the formula (II): ##STR12## wherein: R₂₁ is cyano;R₂₂ is S(O)_(m) R₂₃ ; R₂₃ is alkyl or haloalkyl; R₂₄ is --N═C(R₂₅)N(R₂₆)(R₂₇); R₂₅ is hydrogen, alkyl, or alkyl substituted by one or more halogen, alkoxy, haloalkoxy or --S(O)_(m) R₃₅ ; R₂₆ and R₂₇ each independently are hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₃₅ ; or alkyl substituted by phenyl or pyridyl each of which ring is optionally substituted with one or more members selected from the group consisting of halogen, nitro and alkyl; with the proviso that at least one of R₂₆ and R₂₇ is alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or --S(O)_(m) R₃₅, or at least one of R₂₆ and R₂₇ is alkyl substituted by phenyl or pyridyl each of which ring is optionally substituted with one or more members selected from the group consisting of halogen, nitro and alkyl; X is nitrogen or C-R₃₂ ; R₂₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or --S(O)_(t) R₃₀ ; R₃₀ is alkyl or haloalkyl; R₃₁ and R₃₂ are, independently, halogen, hydrogen, CN or NO₂ ; R₃₃ is halogen, haloalkyl, haloalkoxy, --S(O)_(r) CF₃, or --SF₅ ; R₃₅ is alkyl or haloalkyl; m and r are, independently, 0, 1 or 2; and t is 0 or 2; or a veterinarily acceptable salt thereof.
 11. The method according to claim 10, wherein R₂₂ is SCF₃, R₃₁ is Cl; X is C-Cl; R₃₃ is CF₃ or SF₅ ; R₂₇ is H; R₂₅ is hydrogen or alkyl; and R₂₆ is alkyl substituted by halogen, alkoxy, haloalkoxy or dialkylamino.
 12. The method according to claim 11, wherein R₂₅ is hydrogen or methyl.
 13. The method according to claim 11, wherein R₂₆ is CH₂ CF₃, (CH₂)₂ CF₃, CH₂ OCH₃, (CH₂)₂ OCF₃, (CH₂)₂ OCH₃ or (CH₂)₂ N(CH₃)₂.
 14. The method according to claim 13, wherein R₂₅ is hydrogen or methyl.
 15. The method according to claim 14, wherein R₃₃ is CF₃, R₂₅ is hydrogen and R₂₆ is CH₂ CF₃.
 16. The method according to claim 10, wherein R₂₂ is SCF₃, SO₂ CF₃ or SOCF₃ ; R₃₁ is Cl; X is C-Cl or N; R₃₃ is CF₃ or SF₅ ; R₂₅ is hydrogen or methyl; R₂₆ is CH₂ CN, benzyl, CH₂ CF₃, 2-propynyl, 2-propenyl, CH₂ OC₂ H₅, CH₂ OCH₂ CF₃, CH₂ CH₂ CF₃, (CH₂)₃ CF₃, (CH₂)₂ N(CH₃)₂, 4-chlorobenzyl, CH₂ SO₂ CF₃, (4-pyridyl)methyl, 3-nitrobenzyl or CH₂ CH₂ SCH₃ ; and R₂₇ is hydrogen or methyl.
 17. The method according to claim 16, wherein R₂₅ is H, X is C-Cl and R₃₃ is CF₃.
 18. The method according to claim 17, wherein:(a) R₂₂ is SCF₃, R₂₆ is CH₂ CN and R₂₇ is H; (b) R₂₂ is SOCF₃, R₂₆ is benzyl and R₂₇ is H; (c) R₂₂ is SCF₃, R₂₆ is benzyl and R₂₇ is H; (d) R₂₂ is SOCF₃, R₂₆ is CH₂ CF₃ and R₂₇ is H; (e) R₂₂ is SO₂ CF₃, R₂₆ is 2-propynyl and R₂₇ is H; (f) R₂₂ is SO₂ CF₃, R₂₆ is benzyl and R₂₇ is H; (g) R₂₂ is SO₂ CF₃, R₂₆ is CH₂ CF₃ and R₂₇ is H; or (h) R₂₂ is SCF₃, R₂₆ is CH₂ CF₃ and R₂₇ is H.
 19. The method according to claim 10, wherein the animal is a domestic animal.
 20. The method according to claim 19, wherein the domestic animal is a cat or dog.
 21. The method according to claim 10, wherein the compound of formula (II) is orally administered to the animal in a dosage range of from 0.1 to 500 mg/kg.
 22. The method according to claim 10, wherein the compound of formula (II) is administered at a frequency of from about once per week to about once per year.
 23. The method according to claim 21, wherein the compound of formula (II) is administered at a frequency of about once per week to about once per year.
 24. A composition comprising a parasiticidally effective, substantially non-emetic amount of a compound having formula (II) as claimed in claim 1, or a veterinarily acceptable salt thereof, and a veterinarily acceptable carrier therefor.
 25. A veterinary composition comprising, in oral unit dosage form:(a) a parasiticidally effective, substantially non-emetic amount of a compound having formula (II) as claimed in claim 1, or a veterinarily acceptable salt thereof; and (b) a veterinarily acceptable carrier therefor.
 26. A veterinary composition according to claim 25, wherein the oral unit dosage amount of the compound of formula (II) is from 0.1 to 500 mg per kg of animal body weight. 